Recent morphologic studies of brain specimens obtained from relative y y without a diagnosis of amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC), have shown a remarkably high percentage of individuals with severe widespread neurofibrillary tangle formation and other features of neurodegenerative disease. Indeed, our preliminary data suggests that a majority of Guamanian Chamorro dying between the ages of 50 and 64 show a severe degree of neurofibrillary tangle formation-in the entorhinal cortex and hippocampus. In this project we will investigate this phenomenon further. Primarily through the office of the Medical Examiner of Guam we propose to collect and examine additional brain -specimens derived from residents of Guam, age 30 and above, who die of causes unrelated to ALS/PDC. In these specimens we will determine the extent and distribution of neurofibrillary tangles and other features of neurodegenerative diseases. In our preliminary studies, we have found that the older the individual, the closer the extent and pattern of neuropathologic involvement resembles that of clinically diagnosed cases of ALS/PDC. Based on this and other findings, we believe that the relatively young Guamanians that we have found demonstrating premature widespread neurofibrillary tangle formation represent individuals in its earliest preclinical stages of ALS/PDC but have yet to accumulate a sufficient burden of neurodegenerative lesions to manifest an extent of necrologic and/or cognitive symptomatology needed to attract clinical attention and eventual diagnosis. We will also use immunohistochemical approaches to search for early changes in tan protein immunoreactivity within neuronal populations which are targeted for subsequent neurofibrillary tangle formation. We present evidence to suggest that ALS/PD is not confined exclusively to the indigenous Chamorro population and may also be seen in migrants to Guam with long term residence on the island. We will investigate the influence of long-term exposure to the environment on Guam by investigating brains derived from neurologically in tact Filipinos and US mainland Caucasians migrants to Guam with long-term residence. Finally, through the use of retrospective next-of-kin questionnaires of individuals studied above and prospective longitudinal necrologic and cognitive evaluation of a cohort of 200 elderly Chamorros without ALS/PDC, we will determine if the development of this extensive degree of lesion burden is associated with recognizable clinical deficits.